The cytokine tumor necrosis factor-α (TNFα) plays a role in the induction of inflammatory reactions and is known to be cytotoxic towards tumor cells. TNFα, however, also may cause severe damage to the human body when produced in excess by eventually leading to multiple organ failure and death. See Bemelmans et al., “Tumor Necrosis Factor: Function, Release and Clearance,” Crit. Rev. Immun. 16: 1-11 (1996).
Tumor necrosis factor-α is produced by activated cells, such as mononuclear phagocytes, T-Cells, B-Cells, mast cells and NK cells. TNFα exists in two forms: a type II membrane protein having a relative molecular mass of 26 kD and a soluble 17 kD form generated from the membrane form by proteolytic cleavage. The TNFα membrane protein is synthesized as a 223 amino acid membrane-anchored precursor. The soluble TNFα is released from the membrane-bound precursor by a membrane-anchored proteinase. This proteinase was recently identified as a multidomain metalloproteinase called TNFα-converting enzyme (TACE). See, Black et al., “A metalloproteinase disintigrin that releases tumor-necrosis factor-α from cells,” Nature 385. 729-733 (1997), Moss et al., “Cloning of a disintigrin metalloproteinase that processes precursor tumor-necrosis factor-α,” Nature 385: 733-736 (1997). TACE has recently been identified as a zinc endopeptidase consisting of an extracellular region comprising an N-terminal signal peptide, a pro-domain, a 263 residue catalytic domain (TCD) that is preceded by a furin cleavage site (residues 211-214), a disintegrin domain, an EFF-like domain, and a crambin-like domain, an apparent transmembrane helix and the intracellular C-terminal tail. Tumor necrosis factors converting enzyme (TACE), including a polynucleotide sequence, is described in detail in the published PCT application No. WO 96/41624, herein incorporated in the entirety by reference.
As noted above, the over-production or unregulated production of TNF-α presents serious physiological dangers. It has been implicated in various deleterious physiological diseases such as rheumatoid arthritis, cachexia and endotoxic shock. It also may eventually lead to organ failure and death. Thus, a way to control or block release of TNFα into the circulation is needed. Because of TACE's role in the conversion of TNFα, inhibition, modulation, or regulation of TACE would affect the release of TNFα into circulation. Inhibitors of metalloproteinases and structure based design thereof are described in Zask et al., “Inhibition of Matrix Metalloproteinases: Structure Based Design” Current Pharmaceutical Design, 2:624-661 (1996). Thus, compounds that associate with TACE, such as inhibitors, receptors or modulators will be useful to protect patients from adverse effects associated with the over-production or unregulated production of tumor necrosis factor-α.